COVID-19 Clinical Trials and Expanded Access

EC CORONACOLCHI is a multicenter, double-blind and randomized clinical trial with twobranches. Patients who meet all the inclusion criteria and none of the exclusion criteriawill be randomized 1: 1 to be included in one of the following groups: - Experimental group: colchicine for 2 weeks orally at the doses described, added to the standard treatment of COVID-19. - Control group: placebo for 2 weeks orally added to standard COVID-19 treatment.

Preliminary data suggest that inactivated vaccine-induced neutralizing antibodies againstSARS-CoV-2 decrease at six months after vaccination. Observational, unpublished data alsoindicate that vaccine effectiveness against Covid-19 wanes over time. Thus, theinvestigators aimed to determine the reactogenicity, safety, and immunogenicity of ahomologous or heterologous booster of SARS-CoV-2 vaccines among people already immunizedwith an inactivated SARS-CoV-2 vaccine. The study focuses on the elderly population andhealthcare workers.

T-cell exhaustion may limit long-term immunity in COVID-19 patients. T cells can losetheir ability to fight viruses and tumors when they have prolonged exposure to theseenemies. New data suggests people who experience mild COVID-19 symptoms show themolecular signs of exhausted memory T cells and therefore could have a reduced ability tofight reinfection. On contrary people who develop severe COVID-19 symptoms may be betterprotected from reinfection. A recent study reported that the 82.1% of COVID-19 casesdisplayed low circulating lymphocyte counts . It has been reported that, in the case ofchronic viruses, continuous PD-1 expression causes T-cell exhaustion, and impairs theability of killing the infectious cells . The adumbration of patients with COVID-19 ischaracterized by a diminished lymphocyte percentage, with a similar proportion of CD4+and CD8+ T-cells. The quantity of T-cells, mostly CD8+ T-cells, presenting highexpression rates of late activity marker CD25 and exhaustion marker PD-1 increases.Therefore, SARS-CoV-2 is able to make changes by modifying the acquired immune system,including B and T cells. According to experiments, PD-1's expression, as an importantfactor in the induction and maintenance of circumferential tolerance keeping thestability of T-cells, has been found to have a higher percentage in different cells ofCOVID-19 patients. In an experiment conducted by Diao et al., on the patients withSARS-CoV-2, it was observed that the expression of PD-1 on the surface of T-cells wasincreased significantly; it was also shown that during the SARS-CoV-2 -induced disease,additional expressions of PD-1 and Tim-3 on the T-cells were directly related to thedisease's severity; the factors that were also increased in other viral infections. Tcell exhaustion" phenomenon could be reversed relatively easily, for example when the Tcells are no longer exposed to the virus or tumor. But unfortunately, although exhaustedT cells recovered from chronic infection (REC-TEX) regain some function and features ofmemory T cells (TMEM), they retain epigenetic scars indicating the control of geneexpression is "locked in" to their exhaustion history. Once T cells become exhausted,they remain fundamentally 'wired' to be exhausted-thus it may be hard to get them tobecome effective virus- and cancer-fighters again," said John Wherry, PhD, chair of thedepartment of Systems Pharmacology and Translational Therapeutics and director of thePenn Institute of Immunology in the Perelman School of Medicine at the University ofPennsylvania. Furthermore, COVID-19 may infect T lymphocyte cells and induce apoptosisand apoptotic markers. Lymphocytopenia was also found in the Middle East respiratorysyndrome (MERS) cases. MERS-CoV can directly infect human primary T lymphocytes andinduce T-cell apoptosis through extrinsic and intrinsic apoptosis pathways, but it cannotreplicate in T lymphocytes. However, it is unclear whether SARS-CoV-2 can also infect Tcells, resulting in lymphocytopenia. A study showed that T cells express a very lowexpression level of hACE2 on its cell surface and T-cell lines were significantly moresensitive to SARS-CoV-2 infection when compared with SARS-CoV . In other words, theseresults tell us that T lymphocytes may be more permissive to SARS-CoV-2 infection.Therefore, it is plausible that the S protein of SARS-CoV-2 might mediate potentinfectivity, even on cells expressing low hACE2, which would, in turn, explain why thetransmission rate of SARS-CoV-2 is so high. Through recent advances in genomic editing, Tcells can now be successfully modified via CRISPR/Cas9 technology. For instance, engaging(post-)transcriptional mechanisms to enhance T cell cytokine production, the retargetingof T cell antigen specificity or rendering T cells refractive to inhibitory receptorsignaling can augment T cell effector function. Therefore, CRISPR/Cas9-mediated genomeediting might provide novel strategies for inducing long term immunity againstCOVID-19.Immunotherapies with autologous T cells have become a powerful treatment optionfor many diseases like viral infection or cancer. These include the adoptive isolationand transfer of naturally-occurring virus/tumor-specific T cells and the transfer of Tlymphocytes that have been genetically modified . According to the investigator,exhausted virus-reactive CD8+ memory T cells will be isolated from patients with mildinfection using a modified antigen-reactive T cell enrichment (ARTE) assay. exhaustedvirus-reactive CD8+ memory T cells will be collected and both Programmed cell deathprotein 1(PDCD1) gene and ACE2 gene will be knocked out by CRISPR Cas9 in the laboratory.The lymphocytes will be selected and expanded ex vivo and infused back into patients.

The main objectives of ECCO-2 are: 1) Efficacy: to study whether EQUINACEA ARKOPHARMA,hard caplets containing cryogenized root of the plant Echinacea purpurea, show animprovement of the clinical manifestations and disease course in ambulatory patients withcovid-19 with a respiratory presentation and not requiring hospitalization (i.e., mildcovid-19). The drug being evaluated will be added as a supplement of the standardtreatment, with its current recommended dose for treatment of the common cold. 2) Safety:to determine that the incidence of adverse events is not higher than that seen with thestandard treatment applied in each case.

This study is a multi-centre, blinded, randomized controlled trial. LTCF residents ≥ 65years who have received three doses of mRNA vaccine will be randomized to vaccinationwith a fourth dose of Pfizer-BioNtech mRNA- COVID-19 vaccine or to vaccination with acontrol (Prevnar-13 vaccine).

SOLIDARITY Finland Long-COVID trial assesses the effects of remdesivir + standard of care(SoC) vs. only SoC on long-COVID symptoms and quality of life (QoL) using questionnairesat one and two years post-discharge.Objectives i) Long-COVID symptoms - To investigate the effect of remdesivir (vs. SoC) on the occurrence of symptoms that have been associated with the long-COVID syndrome. The questionnaires will take place 1 and 2 years after the hospital admission. - The symptom questionnaire - that will be completed by patients at one and two years - measures basic patient information (age, height, weight, smoking status, major comorbidity, and working status) and a wide variety of potential long-COVID-symptoms and their bother (1. Fatigue; 2. Attention deficits; 3. Memory problems; 4. Sleeping difficulties; 5. Depressive mood; 6. Anxiety; 7. Dizziness; 8. Headache; 9. Tinnitus; 10. Paresthesias; 11. Changes in taste/smell perceptions; 12. Postexertional malaise; 13. Palpitations; 14. Chest discomfort; 15. Nausea; 16. Skin rash; 17. Joint aches; 18. Muscle pains; 19. Continuous cough; 20. Respiratory tract mucous discharges) in remdesivir and usual care armsii) Quality of life - EQ-VAS: to compare patients' quality of life in remdesivir and usual care arms. - EQ-5D-5L questionnaire assesses the following domains: 1. Mobility; 2. Self-care; 3. Usual activities; 4. Pain and discomfort; 5. Anxiety and depression; 6. The VAS of subjective perception of overall health.Additionally (at 1 or 2 years; depending on future funding and ethical approvaldecisions; currently the study has ethical approval for long-COVID and quality of lifeassessments only): - The Finnish healthcare registries (Statistics Finland Mortality Database and the HILMO Care Register for Health Care) will be used to estimate long-term mortality and incidence of major comorbidity in remdesivir and usual care arms - Lung function will be assessed using spirometry and diffusing capacity, as well as the six-minute walk test (6 mwt) in remdesivir and usual care arms - Whole-genome genotyping will be performed for a genome-wide association study to investigate genetic correlates of long-COVID-19 -symptoms in remdesivir and usual care armsUPDATE 02.02.2022:Primary outcomes will comprise the following: 1. EQ-VAS 2. EQ-5D-5L, summary 3. Does the patient feel recovered from COVID-19-infection at one year or not? (question no. 10) 4. Fatigue (questionnaire, question no. 14) 5. Exertional dyspnea (question no. 12)

The main aim of the study is to estimate the potential efficacy of i.v. canrenone asadd-on therapy on maximal medical treatment versus maximal medical treatment alone intreating moderate-to-severe ARDS due to SARS-CoV-2.

This is an open-label, randomized, multi-centre study where hospitalized subjects will berandomized in a 2:1 ratio to receive Isoquercetin (IQC-950AN) in addition to standard ofcare or standard of care only for 28 days following confirmation of a COVID-19 infection.

This study is an open-label, single-arm study to evaluate the safety and efficacy ofAstrostem-V, allogenic adipose tissue derived mesenchymal stem cells (AdMSC), in patientswith COVID-19 pneumonia. After each subject completes 12-Weeks visit (Visit 12) and thedata management team confirms all individual data have no issue, the individual databasewill be locked and the blinding will be open for the statistical analysis.

Despite enormous progress in understanding COVID-19, there is little evidence that asolution, therapeutic or preventive, is close to being achieved. Repurposing of wellknown, widely available drugs represent an attractive approach to speed up availabilityof active treatments. Such substances as i.e. hydroxychloroquine and others, are alreadyunder investigation and in widespread off label use. For many reasons Methylene blue(MB), the oldest synthetic substance in medicine (1876 synthesized by BASF) is such apromising candidate for an active treatment against SARS-CoV-2 infected people and forCOVID-19 patients.